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    Summary
    EudraCT Number:2006-005186-18
    Sponsor's Protocol Code Number:S187.3.004
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-05-29
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2006-005186-18
    A.3Full title of the trial
    Open-Label, 6-12 Months Safety and Efficacy Study of Levodopa – Carbidopa Intestinal Gel in Levodopa-Responsive Subjects with Advanced Parkinson's Disease and Severe Motor-Fluctuations
    A.4.1Sponsor's protocol code numberS187.3.004
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSolvay Pharmaceuticals B.V.
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name DUODOPA®Intestinal Gel
    D.2.1.1.2Name of the Marketing Authorisation holderSolvay Pharmaceuticals GmbH
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/01/035
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Gel
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPGastroenteral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLevodopa
    D.3.9.1CAS number 59-92-7
    D.3.9.3Other descriptive namePhEur.: (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCarbidopa Monohydrate
    D.3.9.1CAS number 38821-49-7
    D.3.9.3Other descriptive namePhEur.: (2S)-3-(3,4-dihydroxyphenyl)-2hydrazino-2methylpropanoic acid
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatment of levodopa-responsive Parkinson's subjects with severe motor fluctuations.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10013113
    E.1.2Term Disease Parkinson's
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study will be to provide further evidence of the long-term safety and tolerability of levodopa-carbidopa intestinal gel (Duodopa®) over 6-12-months in subjects with advanced Parkinson’s Disease (PD) and severe motor-fluctuations who have not had optimal response to oral levodopa-carbidopa treatment. Additional supportive evidence for efficacy will be assessed in the treatment of severe motor-fluctuations, dyskinesia and mobility.
    E.2.2Secondary objectives of the trial
    A secondary objective is to assess the long-term maintenance of efficacy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of idiopathic Parkinson’s disease according to the United Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria with the diagnosis made at least 2 years prior to enrollment in the study.
    2. The subject’s Parkinson’s disease must be the levodopa-responsive type as judged by the investigator; additionally, subjects will need to demonstrate severe motor fluctuations in spite of individually optimized treatment, and where other therapy options beside oral treatment are indicated.
    3. Subjects have had optimal treatment with available PD medication as defined by local standards of care and, based upon the judgment of the investigator, are judged
    inadequately controlled on this optimized treatment.
    4. Presence of a recognizable “off” and “on” state (motor fluctuations) as confirmed by diary at baseline (diary measurements performed for the three days preceding the baseline visit).
    5. Subjects or subject’s proxy/caretaker must be able to keep a subject diary of “off” time.
    6. Minimum “off” time must be approximately 3 hours per day as estimated by the investigator.
    7. The subject must be able to understand the nature of the study and must provide written informed consent prior to the conduct of any study procedures (including any changes occurring in the subject’s current therapeutic regimen).
    8. Subjects must be able to speak, read, understand and possess the ability to respond to and follow simple instructions in their native language and/or in English. All required documents, including the informed consent, will be translated into the native language as appropriate.
    9. Male or female subjects aged at least 30 years
    10. Females who are not breast-feeding or are of non-childbearing potential may be enrolled. All females of child bearing potential must have a negative serum beta-human chorionic gonadotropin (β-HCG) test prior to study entry.
    Non-childbearing is defined as:
    -last natural menstruation at least 24 months prior to baseline, or
    -surgically sterilized (i.e. bilateral tubal sterilization) at least three months prior to
    baseline, or
    -total hysterectomy at least three months prior to baseline
    11. A female subject of child-bearing potential may be enrolled provided that she is maintained on a medically acceptable method of birth control.
    E.4Principal exclusion criteria
    Subjects meeting any of the exclusion criteria listed below either at screening and/or baseline must be excluded from participation in the study.

    1. Diagnosis is unclear or a suspicion of other Parkinsonian syndromes exists, such as secondary Parkinsonism (caused by drugs, toxins, infectious agents, vascular disease, trauma, brain neoplasm), Parkinson-plus syndromes (e.g., multiple system atrophy, progressive supranuclear palsy) or the other neurodegenerative diseases;
    2. Subjects who have undergone surgery for the treatment of PD (e.g., pallidotomy, deep brain stimulation, fetal tissue transplantation);
    3. Subjects with any neurological deficit that might interfere with the study assessments (e.g. hemiparesis); and/or any subjects who have had a stroke in the last two years;
    4. Treatment with prohibited medications
    5. Known hypersensitivity to levodopa, carbidopa or radiopaque material;
    6. Contraindications to levodopa, such as narrow angle glaucoma, hyperthyroidism,
    pheochromocytoma, Cushing’s syndrome and history of malignant melanoma;
    7. Subjects who are experiencing sleep attacks or who exhibit clinically significant impulsive
    behavior (e.g. pathological gambling, hypersexuality).
    8. Current diagnosis or history of drug or alcohol abuse (Diagnostic and Statistical Manual of
    Mental Disorders [DSM]-IV-TR criteria) within 12 months prior to screening visit;
    9. Current primary psychiatric diagnosis of acute psychotic disorder or other primary
    psychiatric diagnoses, such as bipolar disorder or major depressive disorder (DSM-IV-TR
    criteria);
    10. Psychiatric, neurological or behavioral disorders that may interfere with the ability of
    subjects to give informed consent, or interfere with the conduct or interpretation of the
    study; troublesome hallucinations would also be included under this category;
    11. Alzheimer’s disease; or other significant cognitive impairment or dementia (defined as
    [MMSE] <24).
    12. Clinically significant abnormal laboratory data (e.g., aspartate aminotransferase [AST] or
    alanine aminotransferase [ALT] greater than three times the upper limit of normal) or any
    abnormal laboratory value that could interfere with the assessment of safety in the
    judgment of the investigator;
    13. Current evidence of clinically significant hematological, autoimmune, endocrine,
    cardiovascular, renal or gastrointestinal disorder that would possibly interfere with the
    subject’s participation in the study (e.g., treated, controlled and thus stable hypertension is
    not considered an exclusion criterion);
    14. A history of, or a known current gastrointestinal, liver, kidney or other known condition, which may interfere with the absorption, distribution, metabolism or excretion of the study medication and/or assessments, or interfere with the insertion of the tubing system (e.g., subjects who have undergone gastric or intestinal surgery other than, for instance, appendectomy or cholecystectomy);
    15. Any malignant disease or a history of neoplasms, other than carcinoma in situ of the cervix or basal cell carcinoma of the skin, within the past five years prior to screening; Additionally, subjects with prostate cancer may be considered for enrollment in the study following a comprehensive assessment and a discussion between the Investigator and the Medical Monitor regarding the appropriateness of the subject for the study;
    16. Medical, laboratory or surgical issues deemed by the investigator to be clinically significant;
    17. A planned surgical procedure scheduled for when a subject would be participating in the study (subjects may later be considered for inclusion following full recuperation from the surgical procedure).
    18. Exposure to any investigational drug within 30 days prior to baseline;
    19. Prior exposure to levodopa-carbidopa gel;
    20. Uncooperative attitude or reasonable likelihood for non-compliance with the protocol;
    21. Site personnel and their immediate families defined as spouse, parent, child, grandparent or grandchild; or
    22. Subjects who will not provide written informed consent for participation in the study.
    23. Subjects for whom placement of a PEG-J tube for levodopa/carbidopa intestinal gel treatment is contraindicated, or that the subject would be considered a high risk for the PEG-J procedure, according to the gastroenterologist’s evaluation. Contraindications for PEG-J tube placement include, but are not limited to, the following conditions: pathological changes of the gastric wall, inability to bring the gastric wall and abdominal wall together, blood coagulation disorders, peritonitis, acute pancreatitis, and paralytic ileus.
    E.5 End points
    E.5.1Primary end point(s)
    Safety and tolerability will be assessed by changes from baseline in:
    - Physical examination including weight
    - Vital signs: systolic/diastolic blood pressure, pulse rate and temperature including orthostatic vital signs (supine and standing [after two minutes])
    - Clinical laboratory assessments including biochemistry (sodium [Na], potassium [K], chloride [Cl], blood urea nitrogen [BUN], bicarbonate, creatinine [Cr], creatine kinase [CK], glucose, gamma-glutamyl transferase [GGT], calcium [Ca], aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], total bilirubin, lactate dehydrogenase [LDH], total protein, uric acid, total cholesterol, triglycerides, and blood alcohol), hematology (complete blood count [CBC] with differential, red blood cell [RBC], platelet counts, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH] and mean corpuscular hemoglobin concentration MCHC) and urinalysis (dipstick). Thyroid function studies ((including TSH, and free T4 from serum) will be performed only at screening and pregnancy testing (serum β-HCG) will be performed on women of childbearing potential at screening and every 12 weeks thereafter.
    - Resting 12-lead electrocardiogram (ECG)
    - Concomitant medication use
    - Adverse Event monitoring (including sleep attacks, for the development of melanoma or impulsive behavior)
    - Monitoring complications of the infusion device
    - Abnormal Involuntary Movement Scale (AIMS)
    - Premature study terminations

    Efficacy will be assessed by:
    - Change from baseline in mean daily “off” time (hours), based on a self-administered home diary assessment of motor state on three consecutive days at multiple intervals.
    - Change from baseline in the diary based assessment of “on” time with troublesome dyskinesia, and “on” time without troublesome dyskinesia
    - Clinical Global Impression-Improvement (CGI-I) scores
    - Unified Parkinson’s Disease Rating Scale (UPDRS) total score and sub-scores of parts I-III. Practically defined “off” time (pre am dose) and best “on” time (1-2 hours post dose) and Part IV (subscore Dyskinesia items)
    - Total score Parkinson’s Disease Questionnaire-39 (PDQ-39)

    Pharmacokinetics: Whole blood samples (6 mL per sample) will be obtained for the determination of plasma concentrations of levodopa.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Information not present in EudraCT
    E.6.8Bioequivalence Information not present in EudraCT
    E.6.9Dose response Information not present in EudraCT
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA52
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 250
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-06-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-09-25
    P. End of Trial
    P.End of Trial StatusCompleted
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